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Background: Increased renal sodium avidity is a hallmark feature of the heart failure syndrome. Summary: Increased renal sodium avidity refers to the inability of the kidneys to elicit potent natriuresis in response to sodium loading. This eventually causes congestion, which is a major contributor to hospital admissions and mortality in heart failure. Key Messages: Important novel concepts such as the renal tamponade hypothesis, accelerated nephron loss, and the role of hypochloremia, the sympathetic nervous system, inflammation, the lymphatic system, and interstitial sodium buffers are involved in the pathophysiology of renal sodium avidity. A good understanding of these concepts is crucially important with respect to treatment recommendations regarding dietary sodium restriction, fluid restriction, rapid up-titration of guideline-directed medical therapies, combination diuretic therapy, natriuresis-guided diuretic therapy, use of hypertonic saline, and ultrafiltration.

In a state of normal physiology, the human body adeptly responds to extracellular volume expansion resulting from increased dietary sodium intake. Multiple pathways are intricately modulated to augment the glomerular filtration rate (GFR) and fractional sodium excretion in such cases, thereby maintaining euvolemia. In heart failure (HF), these regulatory mechanisms fail, causing sodium retention and extracellular fluid overload. Mechanistic studies have shown that the GFR – and thus the amount of filtered sodium – appropriately increases after sodium loading in HF, yet the fractional sodium excretion actually diminishes [1]. Subsequent investigations have demonstrated that urine sodium concentrations are lower in HF and this may predict episodes of acute decompensated HF (ADHF). Furthermore, impaired responses to diuretics are frequent. While a urine output >3 L is typical with 40 mg of furosemide in healthy subjects, such response is rarely achieved in HF [2]. Collectively, these observations have led to the recognition that increased renal sodium avidity is a hallmark feature of the HF syndrome. In this review, an update on novel concepts regarding its pathophysiology and management is provided.

We have previously reviewed in detail how different segments of the nephron contribute to renal sodium avidity in HF [3]. These mechanisms are summarized in Table 1. More recently, novel concepts in the pathophysiology of renal sodium avidity have been described (Fig. 1).

Table 1.

Contributions of different nephron segments to increased renal sodium avidity in HF

Nephron segmentPathophysiological changes in HF
Glomerulus ↑ filtration fraction (= GFR/renal blood flow) because of the following: 
• ↓ renal blood flow 
• predominant efferent over afferent vasoconstriction through neurohumoral activation 
Proximal tubule ↑ sodium reabsorption because of the following: 
• ↑ colloid oncotic and ↓ hydrostatic pressure in peritubular capillaries (due to ↑ filtration fraction) 
• ↓ colloid oncotic pressure in the renal interstitium because of increased lymph flow 
• more pronounced with lower renal blood flow 
Loop of Henle ↑ sodium reabsorption because of neurohumoral activation with stimulation of the natrium/kalium/chloride symporter 
Distal convoluted tubules, collecting tubules, and collecting ducts ↑ sodium reabsorption because of neurohumoral activation with stimulation of the natrium/chloride symporter and epithelial sodium channels 
Nephron segmentPathophysiological changes in HF
Glomerulus ↑ filtration fraction (= GFR/renal blood flow) because of the following: 
• ↓ renal blood flow 
• predominant efferent over afferent vasoconstriction through neurohumoral activation 
Proximal tubule ↑ sodium reabsorption because of the following: 
• ↑ colloid oncotic and ↓ hydrostatic pressure in peritubular capillaries (due to ↑ filtration fraction) 
• ↓ colloid oncotic pressure in the renal interstitium because of increased lymph flow 
• more pronounced with lower renal blood flow 
Loop of Henle ↑ sodium reabsorption because of neurohumoral activation with stimulation of the natrium/kalium/chloride symporter 
Distal convoluted tubules, collecting tubules, and collecting ducts ↑ sodium reabsorption because of neurohumoral activation with stimulation of the natrium/chloride symporter and epithelial sodium channels 
Fig. 1.

Novel concepts in the pathophysiology of renal sodium avidity in HF.

Fig. 1.

Novel concepts in the pathophysiology of renal sodium avidity in HF.

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Renal Tamponade Hypothesis

The renal parenchyma is enclosed by a rigid capsule, a layer of fat, and the peritoneal space. Factors exerting elevated pressures in either one of these (i.e., venous congestion, obesity, or ascites) therefore translate into increased renal interstitial pressure. Animal models where the renal vein is clipped have confirmed an almost instantaneous increase in renal interstitial pressure that is associated with a pronounced drop in GFR and urine output, as well as tubular damage [4]. Especially tubular structures in the renal medulla are at risk for damage from venous congestion because their more hypoxic environment makes them particularly vulnerable for impaired perfusion when compared to structures closer to the renal cortex. Furthermore, collapse of the renal venules occurs with a critical intra-capsular pressure overload, which is reflected by discontinuous venous flow patterns on Doppler ultrasonography [5]. Renal decapsulation has shown to alleviate ischemia-reperfusion-induced acute kidney injury in piglets [6], yet no studies subscribing its efficacy in humans have been published to date, which may be an interesting topic for future investigation.

Accelerated Nephron Loss

Chronic elevations in glomerular hydrostatic pressure result in an accelerated loss of functioning nephrons [7]. In HF, the single-nephron GFR often increases to compensate for a loss of nephrons and preserve the overall GFR. However, the consequence is an increased filtration fraction in individual nephrons, imposing strain on the podocytes of the glomerular basement membrane that are critical for nephron survival. Once a critical mass of approximately half a million nephrons has been lost in a kidney, the overall GFR declines more rapidly. Whereas total GFR drops at a rate of <0.5–1 mL/min/1.73 m2 per year with normal aging in healthy individuals, the average decline is about 2.6 mL/min/1.73 m2 in HF [8], where 22% of patients demonstrate slopes >5 mL/min/1.73 m2 [9].

Hypochloremia

Hypochloremia is a common electrolyte disturbance among patients with ADHF, occurring in 13% of patients in the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF) trial [10], 21% in the Randomized, Placebo-controlled, Dose-finding Study of the Adenosine A1 Receptor Antagonist Rolofylline in Patients with Acute Heart Failure and Renal Impairment (PROTECT) trial [11], and 15% in the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial [12]. Increased neurohumoral activation as well as consequences from dietary salt restriction and treatment with diuretics all contribute to its prevalence. Several clinical studies, including post hoc analyses of the aforementioned trials, have linked hypochloremia to diuretic resistance and adverse clinical outcomes [10, 11, 13, 14]. Of all electrolytes, chloride plays the most important role in renal salt regulation. Low tubular chloride levels activate with no lysine kinases, which promote the upregulation of the sodium/potassium/chloride and sodium/chloride symporters that constitute the most important active sodium transporters in Henle’s loop and the distal tubules [15]. Furthermore, chloride influx in macula densa cells lining the tubules at the end of Henle’s loop keeps those cells hyperpolarized. Decreased renal tubular chloride delivery results in depolarization, production of nitric oxide and prostaglandins, which by paracrine effects causes renin release in the adjacent afferent arteriole, with subsequent neurohumoral activation that further promotes proximal tubular sodium reabsorption [3].

Sympathetic Nervous System

The Gauer-Henry reflex suppresses arginine vasopressin and aldosterone with decreased renal sympathetic nerve activity, while atrial natriuretic factor is released, secondary to increased atrial pressures. In HF, this reflex is attenuated and excess renal sympathetic nerve activity is observed despite elevated cardiac filling pressures [16]. Sensory signals originating from the heart, kidneys, and baroreceptors are integrated within the paraventricular nucleus of the hypothalamus to regulate sympathetic nerve outflow [17]. Sensitization of these neuronal pathways by various triggers in HF such as myocardial ischemia, pressure/volume overload, and various endogenous substances (i.e., angiotensin II, adenosine, bradykinin, and hydrogen peroxide) promotes excessive sympathetic nerve activity, contributing to increased sodium and water retention [18]. Many guideline-directed medical therapies (GDMT) for HF target this neurohumoral axis (i.e., β-blockers and renin-angiotensin blockers) to slow the progression of HF. Specific modulation of renal efferent neurons by catheter-based renal denervation augments renal sodium and water excretion in a sheep model of HF, yet more definitive human data are needed [19].

Inflammation

Systemic inflammation is common among HF patients, with 57% of participants in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial showing elevated C-reactive protein levels, which has been linked to disease development, progression, and complications [20]. Sources of inflammation in HF are myocardial ischemia, organ congestion, and hypo-perfusion that activate various components of the innate immune system. This results in activation of nuclear factor kappa B, the nucleotide-binding domain-like receptor protein 3 inflammasome, and expression of pro-inflammatory cytokines such as interleukin-6, interleukin-1b, and intercellular adhesion molecule-1. Other contributors include translocation of endotoxins and bacterial products from the gut; recruitment of pro-inflammatory monocytes from the spleen and adipokines from fat tissue [21]. Beyond deleterious effects on the heart itself, these inflammatory mediators promote renal sodium retention. For example, interleukin-6 stimulates epithelial sodium channels in the distal tubules, which impairs natriuresis and contributes to plasma volume expansion [22]. Lately, there has been much interest to investigate the role of anti-inflammatory agents in the treatment of HF. Intriguingly, responders to the interleukin-1β monoclonal antibody canakinumab, who demonstrated a reduction in C-reactive protein <2 mg/L in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial, experienced a significant 38% reduction in HF hospitalizations [23]. The ongoing Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Heart Failure and Inflammation (HERMES; NCT05636176) trial aims to randomize 5,600 patients with HF and mildly reduced to preserved ejection fraction with high-sensitivity C-reactive protein levels ≥2 mg/L to once-monthly subcutaneous injections of the interleukin-6 monoclonal antibody ziltivekimab 15 mg or placebo, to assess its effect on cardiovascular death, HF hospitalizations, and urgent HF visits.

Lymphatic System

Increased venous pressures, via back-translation of elevated capillary hydrostatic pressures, drive fluid out of the vasculature toward the interstitium. In normal circumstances, the lymphatic system quickly clears and returns this interstitial fluid, preventing edema. With excessive venous congestion, the lymphatic system struggles to overcome its outflow impedance to match the increased capillary filtration, disrupting the fluid balance [24]. The Heart Failure with Preserved Ejection Fraction: Plethysmography for Interstitial Function and Skin Biopsy (HAPPIFY) study has shown that several structural, molecular, and functional derangements contribute to reduced lymphatic reserve in HF [25]. Inadequate lymphatic drainage in turn results in end-organ dysfunction, with congestion of the kidneys leading to further sodium and fluid retention.

Interstitial Sodium Buffers

Based on analyses of skin biopsies from healthy subjects versus patients with HF, it has become clear that the interstitial glycosaminoglycan concentration is significantly increased in the latter group [26]. Because glycosaminoglycans carry multiple negative charges, they attract positively charged sodium ions, acting as an effective buffer in the interstitial space. This reduces the osmolar stress that attracts water into the interstitial compartment, which would lead to edema formation. However, the glycosaminoglycan buffer eventually may become overloaded, resulting in disruption of its architecture, an increase in osmotically active sodium and edema formation. Glycosaminoglycan stores correlate with tissue water content and clinical signs of fluid overload, suggesting their key role in the HF syndrome. Whereas decongestive strategies aim to achieve euvolemia by removing intravascular and interstitial fluid, emptying the interstitial sodium buffer through new therapeutic modalities is an exciting new field [27]. Preliminary data have shown that some of the current neurohumoral blockers, such as spironolactone and sodium-glucose co-transporter-2 inhibitors, may help to mobilize interstitial sodium and restore the interstitial structure and function [28].

Dietary Sodium Restriction

Given that increased renal sodium avidity is a hallmark feature of HF and extracellular volume is governed by sodium homeostasis, a classic recommendation is to prevent fluid overload by dietary sodium restriction. Although seemingly logical, evidence supporting this recommendation has been controversial. In the Study of Dietary Intervention under 100 mmol in Heart Failure (SODIUM-HF) trial, 806 patients were randomly assigned to a low sodium diet (<1,500 mg/day) or usual care [29]. After 12 months, there were no significant differences in all-cause death, cardiovascular-related hospitalizations, or cardiovascular-related emergency department visits between groups. Even though this represents the largest randomized clinical trial addressing the impact of sodium restriction in HF, it should be noted that the observed effect size (11%) and primary outcome event rate (16.1%) were much lower than anticipated (30% and 21.3%, respectively), while the study was stopped early before enrollment of the 992 originally planned participants was completed. Furthermore, actual sodium intake was rather low in both groups, differing only by 415 mg (1,658 mg/day vs. 2,073 mg/day). These limitations clearly impacted on the statistical power of the study. Despite these limitations, improvements in quality of life and New York Heart Association (NYHA) functional class were observed with more strict sodium restriction. A meta-analysis of 1,705 patients from 17 randomized clinical trials showed similar results [30]. Furthermore, a recent systematic review showed the overall paucity of high-quality evidence to support of refute current guidelines on sodium intake [31]. Therefore, current evidence does not allow to argue convincingly for a liberal sodium intake in HF yet at the same time questions the need for strict restriction in every patient, especially with respect to hard clinical outcomes. Finally, there remains a wide gap between guidelines and real-world practice, with only 34% of patients with HF consuming <3,000 mg sodium per day and only 15% consuming <2,000 mg [32].

Importantly, intrinsic renal sodium avidity in HF is a continuum. Some patients with relatively low intrinsic renal sodium avidity (presumably because of less severe disease and better pharmacological treatment) may tolerate liberal dietary sodium intake without risk of decompensation [33]. On the other hand, those patients with high intrinsic renal sodium avidity, especially the ones on maintenance treatment with loop diuretics, may fare better with more strict dietary sodium restriction. Finally, since the ability for natriuresis with intravenous diuretics exceeds any dietary sodium intake by a fair amount, sodium restriction likely is less important during the management of an episode of ADHF.

Fluid Restriction

Although a number of studies have investigated composite care bundles including fluid restriction, only 2 studies have evaluated the isolated effect of fluid restriction alone. Travers et al. [34] randomized 67 hospitalized patients with HF to either fluid restriction ≤1 L/day (achieving a mean fluid intake of 1,074 mL/day) or liberal fluid intake (mean fluid intake 1,466 mL/day). There was no difference in time to clinical stability, discontinuation of intravenous diuretics, or clinical biomarkers including B-type natriuretic peptide. Furthermore, the strategy did not impact on urine output or weight change. Holst et al. [35] randomized 74 ambulatory patients with HF to a 16-week regimen of either fluid restriction ≤1.5 L/day (mean fluid intake 17 mL/kg/day) or a weight-based fluid intake of 30 mL/kg/day with an absolute maximum of 2.4–2.8 L/day (mean fluid intake 23 mL/kg/day). Again, no significant differences between both groups in terms of quality of life, NYHA functional class, or body weight were observed. However, fluid restriction resulted in increased thirst sensation and worse adherence to treatment. The ongoing Fluid Restriction in Heart Failure versus Liberal Fluid Uptake (FRESH-UP) trial (NCT04551729) of fluid restriction ≤1.5 L/day versus liberal intake will provide further insight on the impact of such strategy on quality of life and safety.

From a pathophysiological perspective, it is important to consider that the primary objective of decongestion is the removal of sodium rather than water. Since urine is almost always hypotonic (i.e., lower sodium concentration in urine vs. serum), sufficient amounts of free water are required to achieve sustained natriuresis. Considering this, patients should actually drink at least 1.5 L of water for every 9 g of salt to be removed. Although seemingly controversial at first look, more liberal recommendations such as 30 mL/kg/day may be needed to fully support the renal capacity for natriuresis. Conclusively, current data mainly suggest that a strategy of fluid restriction has no clear benefit in HF. Rather, by increasing thirst, reduced adherence to treatment, and potential compromise of the renal capacity for natriuresis, fluid restriction may put a burden on the overall management of HF. Only in selected patients, such as those with polydipsia or dilutional hyponatremia, fluid restriction may still have a role yet needs more evidence in support.

Rapid Up-Titration of GDMT

The past 2 decades have witnessed major changes in the pharmacological treatment of HF. Current guidelines recommend rapid initiation of GDMT with a sodium-glucose co-transporter-2 (SGLT2) inhibitor and potentially a mineralocorticoid receptor antagonist in all patients, as well as a β-blocker and renin-angiotensin inhibitor in those with a reduced ejection fraction. Each of these classic 4 pharmacological pillars have proven disease-modifying features to reduce HF readmissions and mortality. Intriguingly, all have also shown pleiotropic effects that reduce renal sodium avidity [36]. The Safety, Tolerability and Efficacy of Up-titration of Guideline-directed Medical Therapies for Acute Heart Failure (STRONG-HF) trial has shown the importance of early initiation and rapid up-titration of GDMT after an episode of ADHF [37]. Nonetheless, GDMT still remains largely underutilized in patients with HF for various reasons, including policy-related, clinician-related, and patient-related factors [38]. Addressing these barriers is key to unlock its full potential.

Combination Diuretic Therapy

In contrast to the numerous advances in the pharmacological management of chronic HF, the treatment of ADHF has largely remained the same, with loop diuretics still the mainstay of treatment. However, treatment responses are highly variable and many patients show a suboptimal response to a decongestive strategy with loop diuretics only. In the Diuretic Optimization Strategies Evaluation (DOSE) trial, only 15% of participants were clinically “dry” at 72 h following initiation of intravenous furosemide [39]. It is well known that the maximal efficacy of loop diuretics is attenuated through enhanced proximal and distal sodium reabsorption [40]. Combination diuretic therapy with sequential blockage of these nephron parts may help to achieve greater natriuresis and increase the rate and pace of decongestion (Fig. 2). Two major trials have recently provided important new insights: (1) the ADVOR trial on acetazolamide and (2) the Safety and Efficacy of the Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure (CLOROTIC) trial with hydrochlorothiazide.

Fig. 2.

Combination diuretic therapy with sequential nephron blockage. Acetazolamide acts on the proximal renal tubules by inhibition of carbonic anhydrase (CA), thereby lowering the activity of the sodium/hydrogen exchanger (NHE), resulting in less absorption of sodium and a higher pH of the tubular fluid. Loop diuretics act on the thick ascending limb of Henle’s loop, blocking the sodium/potassium/chloride (NKCC) symporter, thus increasing natriuresis, potassium excretion, and chloride excretion. Thiazide-like diuretics act on the distal convoluted tubules and collecting tubules, increasing sodium and chloride excretion through inhibition of the sodium/chloride (NCC) symporter. ATP, adenosine triphosphate.

Fig. 2.

Combination diuretic therapy with sequential nephron blockage. Acetazolamide acts on the proximal renal tubules by inhibition of carbonic anhydrase (CA), thereby lowering the activity of the sodium/hydrogen exchanger (NHE), resulting in less absorption of sodium and a higher pH of the tubular fluid. Loop diuretics act on the thick ascending limb of Henle’s loop, blocking the sodium/potassium/chloride (NKCC) symporter, thus increasing natriuresis, potassium excretion, and chloride excretion. Thiazide-like diuretics act on the distal convoluted tubules and collecting tubules, increasing sodium and chloride excretion through inhibition of the sodium/chloride (NCC) symporter. ATP, adenosine triphosphate.

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Acetazolamide

Acetazolamide is a carbonic anhydrase inhibitor that reduces sodium reabsorption in the proximal renal tubules, which is the site where at least 60% of all filtered sodium is reabsorbed. In the pilot Diamox to Increase the Urinary Excretion of Sodium: an Investigational Study in Congestive Heart Failure (DIURESIS-CHF) trial of 34 patients with ADHF, the association of acetazolamide to loop diuretics led to a 10–20% increase in natriuresis and a 62% improvement in diuretic efficiency [41]. In the landmark ADVOR trial, 519 adults patients admitted for ADHF with evident signs of fluid overload were randomized to receive either an intravenous bolus of acetazolamide (500 mg once daily) or matching placebo in addition to standardized intravenous loop diuretic therapy (twice the oral maintenance dose daily) [12]. The ADVOR trial demonstrated that upfront acetazolamide use on top of intravenous loop diuretics led to a higher cumulative urine output and natriuresis, greater incidence of successful decongestion (42.2% vs. 30.5% at 72 h), and a shorter length of hospital stay. Several post hoc analyses of the ADVOR trial have confirmed its robust results across the full range of renal function [42] and ejection fraction [43]. The effect of acetazolamide seems magnified when baseline or loop diuretic-induced metabolic alkalosis is present [44].

Thiazide-Like Diuretics

Whereas only approximately 10% of filtered sodium is reabsorbed in the distal convoluted tubule and collecting ducts under normal circumstances, this share can increase considerably with the distal tubular hypertrophy seen with prolonged exposure to loop diuretics [45]. Given this common mechanism of diuretic resistance, thiazide-like diuretics have gained interest as an add-on diuretic option. In the CLOROTIC trial, 230 patients with AHDF were randomized to receive either hydrochlorothiazide or placebo on top of loop diuretics [46]. The hydrochlorothiazide dose was 25 mg daily for a GFR >50 mL/min/1.73 m2, 50 mg daily for 20–50 mL/min/1.73 m2, and 100 mg for <20 mL/min/1.73 m2. Patients receiving hydrochlorothiazide experienced greater weight loss and had a 36% higher median urine sodium excretion at 96 h. Hypokalemia was a common side effect, occurring in 40.6% of patients in the intervention arm. A post hoc analysis showed that the effects of hydrochlorothiazide were attenuated at the lower range of the GFR, yet this may be caused by the rather low dose of hydrochlorothiazide used in the trial [46].

Other Combination Diuretic Treatments

The Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF) trial did not show any improvement in either weight loss or diuresis with high-dose spironolactone (i.e., 100 mg daily) in ADHF [47]. However, many patients in the control group received low-dose spironolactone (i.e., 25 mg daily), potentially diluting the effect size, and the full effect of spironolactone on genomic transcription may take longer than 96 h (when the primary endpoint of the trial was assessed) to kick in. Many studies and trials with SGLT2 inhibitors have shown favorable data in terms of urine output in AHDF [48]. However, the effect on natriuresis is less clear and may need further investigation. Irrespectively of their potential to facilitate decongestion, both mineralocorticoid receptor antagonist and SGLT2 inhibitors are a vital part of GDMT to prevent rehospitalization and mortality in HF. Notably, the Empagliflozin in Patients Hospitalized with Acute Heart Failure who have been Stabilized (EMPULSE) trial has demonstrated a clinical benefit of empagliflozin among 530 patients hospitalized for ADHF, with this benefit defined as a hierarchical composite of death from any cause, number of HF events, time to a first HF event, or a 5-point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days [49].

Natriuresis-Guided Diuretic Therapy

There is large inter-individual variability in intrinsic renal sodium avidity and response to diuretic therapy in HF [33]. This probably results from differences in the severity of the underlying disease, background GDMT, and various pathophysiological mechanisms. A post hoc analysis of the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF) trial showed that classic clinical features could not distinguish between high versus low intrinsic renal sodium avidity [50]. Instead, a spot urine sodium measurement correlated nicely with several decongestion outcomes. Similarly, the group at Yale has demonstrated feasibility of a spot urine sample at 2 h after an initial loop diuretic dose to predict 6-h sodium output [51]. In addition, they found that using such natriuretic response prediction equation to guide loop diuretic titration substantially improved net fluid output and weight loss. A post hoc analysis of the ADVOR trial has also demonstrated that urine sodium concentration strongly predicts successful clinical decongestion [52]. As a result, urine sodium concentration has gained attention as a key metric to assess renal sodium avidity in individual patients with HF. Since it is also an easy, universal, immediate, and readily available metric, it may be used to improve care by intensifying diuretic therapy early in case of an insufficient response. The Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure Study (ENACT-HF) study [53] and Pragmatic Urinary Sodium-based Algorithm in Acute Heart Failure (PUSH-AHF) trial [54] have shown that systematic assessment of post-diuretic urine sodium concentration leads to the use of more intensive diuretic regimens, which increases natriuresis and potentially facilitates decongestion. The ongoing Diuretic Treatment in Acute Heart Failure with Volume Overload Guided by Serial Spot Urine Sodium Assessment (DECONGEST; NCT05411991) and Randomized Controlled Trial of Urine Chemistry Guided Acute Heart Failure Treatment (ESCALATE; NCT04481919) trials are anticipated to further clarify its role.

Hypertonic Saline

Hypertonic saline solution (HSS) has been used to overcome diuretic resistance. It has been hypothesized to act by drawing more water out of the interstitial compartment, thereby improving diuresis without intravascular volume depletion, hence reducing neurohumoral activity. The first evidence of safety and potential efficacy of HSS in ADHF came from a study by Paterna et al. [55], using 150 mL of HSS (NaCl 1.4–4.6%) plus 250 mg of intravenous furosemide twice daily. However, many of the initial studies from these groups have been retracted because the original data were lost. In the Self-Management and Care of Heart Failure (SMAC-HF) trial in 2011, 1,927 patients with ADHF were randomized to HSS with furosemide and a moderate sodium diet versus furosemide alone with a low sodium diet [56]. Results favored the HSS group with a lower risk of cardiovascular mortality, reduced readmission rates, shorter length of hospitalization, and improved NYHA class. Recently, in a group of 58 patients with refractory ADHF, HSS use was associated with increased diuretic efficiency, fluid and weight loss, without important safety concerns [57]. Notably, experience with HSS has been mostly restricted to diuretic-resistant patients with ADHF and refractory symptoms of congestion, who were often receiving high doses of loop diuretics in conjunction with strict fluid and sodium restriction, not unusually on poor background GDMT. Therefore, excessive and potentially preventable neurohumoral activation was present in most HSS studies. Finally, not a single study with HSS in ADHF has shown that this strategy results in a net negative sodium balance. Therefore, it remains unsure what the role of HSS is in contemporary treated patients with HF on GDMT and with the use of combination diuretic therapy. At the moment, it is probably reserved for selected cases with refractory diuretic resistance and hyponatremia.

Ultrafiltration

Ultrafiltration is arguably the most effective method for rapid decongestion. With sodium concentrations in the filtrate that are by definition iso-osmolar, a net negative sodium balance can easily be achieved. Furthermore, ultrafiltration allows a precise adjustment of the amount of fluid removal. The Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) trial [58] provided the first evidence for the efficacy of ultrafiltration in ADHF, suggesting that it allowed greater weight and net fluid loss compared with intravenous loop diuretics, resulting in a significantly reduced 90-day readmission rate. However, the subsequent Cardio-Renal Rescue Study in Acute Heart Failure (CARRESS-HF) trial [59] showed similar weight loss compared to a carefully titrated stepped pharmacological care arm, with more adverse events (predominantly access-related) and a worse serum creatinine evolution in the ultrafiltration arm. Critics raised concerns over the fixed 200 mL/h ultrafiltration rate in the CARRESS-HF versus a very flexible and individually titrated pharmacological care arm. Furthermore, there was a high rate of crossover in this trial. In fact, a per-protocol analysis of the CARRESS-HF did show a difference in weight and fluid loss in favor of ultrafiltration [60]. Therefore, the Aquapheresis versus Intravenous Diuretics and Hospitalization for Heart Failure (AVOID-HF) trial [61] was set up to compare more individually titrated ultrafiltration with intravenous loop diuretics. Unfortunately, this trial had to be stopped early because of a withdrawal of funding, leaving it severely underpowered, yet with a non-significant signal of decreased readmissions for HF in the ultrafiltration arm. As current pharmacological care with combination diuretics is increasingly effective to achieve decongestion, ultrafiltration at the moment probably remains reserved for therapy-refractory patients.

Looking at the future, we anticipate that urine sodium-guided diuretic therapy will probably change the way we treat ADHF. Future investigations will reveal which add-on diuretics to use, in which combinations, and in which specific sequence, depending on circumstances. It should be a goal to produce individualized diuretic regimens that achieve a net negative sodium balance while limiting adverse effects and neurohumoral activation, bringing the promises of personalized medicine to the realm of HF management. Especially given the low cost and easy use of urine sodium measurements, these approaches have a high potential for worldwide adaptation. On the other end of the spectrum, we anticipate the development of highly specific technologies that may intervene on specific pathophysiological mechanisms related to renal sodium avidity in very selected and well-phenotyped cases, such as renal decapsulation, renal artery denervation, agents targeting the lymphatic system and interstitial sodium buffers, and renal hemodynamics pumps. These technologies will come at high costs but may serve very specific scenarios where combination diuretic therapy may not suffice.

Increased renal sodium avidity is a hallmark feature of the HF syndrome. In this review, an update on its pathophysiology and management is provided. The renal tamponade hypothesis, accelerated nephron loss, hypochloremia, the sympathetic nervous system, inflammation, the lymphatic system, and interstitial sodium buffers all play an important role. Furthermore, the role of dietary sodium restriction, fluid restriction, rapid up-titration of GDMT, combination diuretic therapy, natriuresis-guided diuretic therapy, the use of hypertonic saline, and ultrafiltration were discussed. While the treatment of ADHF has largely remained the same in the past couple of decades, recent research provides a momentum to revolutionize the field. Urine sodium-guided combination diuretic therapy as well as novel technologies targeted at specific pathophysiological mechanisms of renal sodium avidity will likely play a major role in this bright future.

The authors have no conflict of interest to declare.

No funding was received.

J.V.dE. wrote the first draft of the manuscript under the supervision of F.H.V. who subsequently revised the manuscript.

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